Targeting Jak3 in the treatment of autoimmune disease

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

Cytokines comprise a large family of secreted proteins that regulate cell growth and differentiation of many types of cells. These factors are especially important in regulating immune and inflammatory responses, regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. Understanding the molecular basis of cytokine action provides important insights into the pathogenesis of immune-mediated disease and offers new therapeutic targets. We discovered human Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). We have received two patents related to targeting Jak3 as the basis for a new class of immunosuppressant/immunomodulatory drugs, and established a Cooperative Research and Development Agreement (CRADA) with Pfizer to generate the first-generation Jak3 antagonists. One compound, tofacitinib (CP 690,550), was produced by Pfizer and found to be effective in preclinical models. The drug was tested in Phase III studies in rheumatoid arthritis, and has now been approved for this indication. Tofacitinib is also being studied in psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile arthritis and transplant rejection. Several other Jak inhibitors have been developed and are also in clinical trials. The CRADA with Pfizer was renewed this year and was directed at better understanding the mechanisms of action of tofacitinib and related inhibitors. Current studies are ongoing, evaluating tofacitinib in models of graft versus host disease. Despite the success of allogeneic hematopoietic stem cell transplantation (HSCT), the complication graft versus host disease (GvHD) remains a significant cause of morbidity and mortality. Adequate treatment of this heterogeneous collection of disorders is an unmet need, and Jak inhibitors might be used in this setting. We have been studying the effects of tofacitinib on a CD8 T-cell-dependent murine model of GvHD, in which keratin 14 promoter-chicken ovalbumin (OVA)-transgenic mice adoptively transferred with CD8 T cells expressing an OVA-specific T cell receptor (OT-I cells). We found that oral administration of tofacitinib completely prevented the GvHD-like disease; more importantly, tofacitinib was also effective in reversing established GvHD-like disease. Treatment of affected mice with tofacitinib diminished the number of OT-I effector cells. This treatment also reduced cytokine and chemokine production, and markers of activation in transferred T cells. These data suggest that tofacitinib may be of utility in the treatment of GvHD. In addition, the data argue for the potential use of other CD8-mediated immune-mediated disorders. In addition, we are studying the effects of tofacitinib on T cell metabolism. T cell activation is associated with a switch to glycolytic metabolism. We have found that tofacitinib inhibits the induction of many key glycolytic enzymes. The interference with cytokine-regulated changes in metabolism may be an important aspect of the mechanism of action of Jak inhibitors.